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AN APPROACH TO SEMI FLEXIBLE DOCKING: A case study of the enzymatic reaction catalysed by terpenoid cyclases DIMACS, 13 June 2005

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Presentation on theme: "AN APPROACH TO SEMI FLEXIBLE DOCKING: A case study of the enzymatic reaction catalysed by terpenoid cyclases DIMACS, 13 June 2005"— Presentation transcript:

1 AN APPROACH TO SEMI FLEXIBLE DOCKING: A case study of the enzymatic reaction catalysed by terpenoid cyclases DIMACS, 13 June 2005 vladimir.sobolev@weizmann.ac.il Vladimir Sobolev Weizmann Institute of Science

2 1. Approach to molecular docking and definition of surface complementarity AN APPROACH TO SEMI FLEXIBLE DOCKING: A case study of the enzymatic reaction catalysed by terpenoid cyclases 2. Modeling first two steps of enzymatic reaction catalysed by terpenoid cyclases

3 1. Approach to molecular docking and definition of surface complementarity AN APPROACH TO SEMI FLEXIBLE DOCKING: A case study of the enzymatic reaction catalysed by terpenoid cyclases 2. Modeling first two steps of enzymatic reaction catalysed by terpenoid cyclases

4 Where is the binding site located?What is the ligand orientation? Relevant Questions for Docking Two Major Algorithmic Issues in Molecular Docking: 2. Search procedure 1. Scoring function

5 CF = S l - S i - E r S l = surface area of legitimate atomic contacts S i = surface area of illegitimate atomic contacts E r = a repulsion term Complementarity Function for molecular docking

6 Definition of Contact Surface Between Atoms R a,R b ~ 1.5-2.0 Å; R w = 1.4 Å Thus, contact appears from R ab ~ 6 Å contact surface of atom A with B is the surface area of sphere A that penetrates sphere B.

7 Definition of Contact Surface Between Atoms In both cases R ab is the same, while in second case there is no contact between atoms A and B

8 Atomic Classes IHydrophilicN or O that donate or accept a hydrogen bond (e.g., O of OH group of Ser or Thr) IIAcceptorN or O that only accept a hydrogen bond (e.g., O of peptide group) IIIDonorN that only donates a hydrogen bond (e.g., N of peptide group) IVHydrophobicCl, Br, I and C atoms not in aromatic rings and not covalently bonded to N or O VAromaticC atoms in aromatic rings VINeutralS, F, P, and metal atoms; C atoms covalently bonded to one or more atoms of class I or two or more atoms of class II or III VIINeutral-donorC atoms that are covalently bonded to only one atom of class III VIIINeut.-acceptorC atoms that are covalently bonded to only one atom of class II

9 Legitimacy (for each pair of contacts) Atomic class IIIIII IVV VI VII VIII IHydrophilic+++ -++++ IIAcceptor+ -+ -+++ - IIIDonor++ - -++ -+ IVHydrophobic - - -+++++ VAromatic++++++++ VINeutral++++++++ VIINeutral-donor++ -+++ -+ VIIINeutral-acceptor+ -+++++ - Hydrophilic Accepto r Donor Hydrophobic Aromatic Neutral Neutral-donor Neutral-acceptor

10 CF = S l - S i - E r S l = surface area of legitimate atomic contacts S i = surface area of illegitimate atomic contacts E r = a repulsion term Complementarity Function for molecular docking

11 Input coordinates, size of search cube, number of initial ligand positions (N), and number of best positions kept (M) Generate random ligand position and orientation in the search cube n = 1 n = n+1 Maximize complementarity function (CF) Keep not more than M best maxima Does n equal N? Yes No. Optimize H-bond lengths for every M structure obtained Cluster maxima Calculate and list contacts for the position with highest complementarity Calculate and list normalized complementarity (CF) following atom substitution Satisfactory CF position found? Yes No Neglect steric clash for a user defined number of residues Flow Chart of LIGIN Program

12 Critical Assessment of Techniques for Protein Structure Prediction http://sgedg.weizmann.ac.il/casp2 Our Results

13 1. Approach to molecular docking and definition of surface complementarity AN APPROACH TO SEMI FLEXIBLE DOCKING: A case study of the enzymatic reaction catalysed by terpenoid cyclases 2. Modeling first two steps of enzymatic reaction catalysed by terpenoid cyclases

14 Chemical scheme of the substrate (farmecyl diphosphate (FFP)

15 Terpenoid cyclases may produce a large number of products from a single substrate. Steele et al., 1998

16 Chemical scheme of the substrate (farmecyl diphosphate (FFP)

17 Flowchart describing semi flexible docking

18 Results of the semi flexible docking for the first stage

19 Residues forming contacts with the leading structure Res.Dist. Å Sur f Å 2 Res.Dist. Å Surf Å 2 Arg2643.232Tyr4043.429 Trp2733.656Leu4073.916 Ile2943.729Cys4403.922 Ile2974.316Ile5154.110 Ser2984.123Val5164.810 Asp3013.028Tyr5203.143 Asp3052.613Asp5252.534 Thr4023.921Tyr5273.948 Thr4034.118

20 Docking prediction for WT pocket and three mutants. Blue - predicted structure; green - experimental one WTV516G Y520GV440G

21 OPP 4 5 6 7 8 9 10 11 14 13 12 15 3 21 Contribution for the complementarity function of all groups of 4 adjacent carbons.

22 OPP 4 5 6 7 8 9 10 11 14 13 12 15 3 21 Contribution for the complementarity function of all groups of 4 adjacent carbons. NCarbon AtomsCOMPLEMENTARITY 1C10 C11 C12 C15116 2C9 C10 C11 C12114 3C3 C4 C14 C5102 4C6 C7 C8 C985 5C3 C4 C5 C681 6C4 C5 C6 C781 7C5 C6 C7 C880 8C9 C10 C11 C1578 9C2 C3 C4 C1477 10C7 C8 C9 C1069 11C8 C9 C10 C1169 12C5 C6 C7 C1353 13C2 C3 C4 C551 14C6 C7 C8 C1350 15C7 C8 C13 C949

23 Scheme for the prediction of the second step of the reaction

24 Analysis of the results of the “second stage” reaction model KN Compl. Max. Compl. Contacts with (C1)Cluster 1107412457Thr402a 296459508Tyr520, Asp444b 316541555Tyr404, Thr403, Thr402c 321534555Tyr520, Asp444d 385519555Trp273e 416601615Trp273f 510677697Trp273e 534661697Trp273g 552655697Tyr404h 72819833Trp273e 91990 Trp273e

25 List of super-groups clustered according to the interaction with carbocation C1 Super-grope number Group letters Contacts with C1 1e, f, gTrp273 2b, dTyr520, Asp44, Asp525 3c, hTyr404, Thr403, Thr402 4aThr402

26 Two candidates for amino acids involved in stabilising the reaction intermediate

27 Summary 1. Docking algorithm was described 2. First two steps of enzymatic reaction catalysed by terpenoid cyclases were modeled. There is already experimental data confirming correctness of the first step model. While modeling second step in the large extent speculative

28 ACKNOWLEDGMENTS Meir Edelman (WIS) Eran Eyal (WIS) Gert Vriend (EMBL) Rebecca Wade (EMBL)

29 AN APPROACH TO SEMI FLEXIBLE DOCKING: A case study of the enzymatic reaction catalysed by terpenoid cyclases DIMACS Workshop, 12 June 2005 vladimir.sobolev@weizmann.ac.il Vladimir Sobolev Weizmann Institute of Science


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